DESCRIPTION: Casein kinase II (CKII) is a highly conserved Ser/thr protein kinase that is ubiquitous in eukaryotic organisms. CKII phosphorylates a broad spectrum of endogenous substrates, including several nuclear oncogene proteins. The activity is elevated in rapidly dividing normal cells, in transformed cells in culture, and in solid human tumors. Unregulated expression of CKII in lymphocytes of transgenic mice has been shown to result in the stochastic production of lymphomas and, in combination with c-myc, in the production of leukemia. A better understanding of the enzyme may provide important insights into normal cell cycle regulation, cell transformation, and cancer. The objective of the proposed research is to determine the physiological role of CKII, using Saccharomyces cerevisiae as a model system. S. cerevisiae CKII has been purified to homogeneity and fully characterized. Genes encoding each of the four subunits have been isolated, null and conditional mutations in these genes have been constructed, and multicopy suppressors of conditional alleles have been isolated. The enzyme is essential for viability and required for cell cycle progression. The specific aims of the work are: 1) to analyze the function of the catalytic and regulatory subunits in vivo via site-directed mutagenesis; 2) to determine the mechanism underlying the salt-sensitive phenotype of regulatory subunit mutants: 3) to define the mechanism of interaction between CKII and two previously characterized extragenic suppressors, CDC37 and ZDS1,2; and 4) to identify additional genes which interact genetically with CKII. The results of the proposed work should illuminate both the physiological role and mechanism of regulation of CKII. Given the high degree of evolutionary conservation of the enzyme, the results should be broadly applicable to CKII from higher organisms, including man.